tbuckley/cabot-search huggingface dataset:
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Authors: Don Barkin
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Helen Salisbury: New telephones, but no one to answer them
Authors: Helen Salisbury
Journal: BMJ (2023)

The Department of Health and Social Care and NHS England published a report last week about how they intend to improve access to primary care. 1 The most concrete elements are funds for new telephone systems and trying to offload some GP work onto community pharmacies.The reception has not been positive, partly because many surgeries are already doing nearly all the things in the plan and are still drowning in patient demand.1 NHS England.Delivery plan for recovering access to primary care.9 May 2023.
An Attempt to Stretch the Benefit: Rechallenge with PARP Inhibitors in Ovarian Cancer
Authors: Eduardo Gonzalez-Ochoa, Amit M. Oza
Journal: Clinical Cancer Research (2023)

Summary PARP inhibitors exploit synthetic lethality in homologous recombination–deficient (HDR) cells and are standard-of-care treatment in newly diagnosed and relapsed epithelial ovarian cancer (EOC). A recent article demonstrated that a second course of olaparib can be safely administered to women with BRCA-mutated EOC. See related article by Morgan et al., p. 2602
What do we know about the Arcturus XBB.1.16 subvariant?
Authors: Mun-Keat Looi
Journal: BMJ (2023)

COVID-19What do we know about the Arcturus XBB.1.16subvariant?The "Arcturus" subvariant of SARS-CoV-2 has been making headlines for weeks.Mun-Keat Looi reports what we know so far Mun-Keat LooiWhat is XBB.1.16? XBB.1.16is yet another in the line of omicron subvariants that began with BA.2.It follows on from XBB and XBB.1 and is related to the XBB.1.5subvariant ("Kraken") that began to dominate at the start of the year. 1 Some have nicknamed this new subvariant "Arcturus" (meaning "Guardian of the Bear" in Greek) to distinguish it from the confusing number of other omicron versions.The X signifies that these subvariants came about through a recombination of two or more sublineages (in this case BA.2.10.1.1 and BA.2.75.3.1.1.1).
Efficacy of mRNA-1273 and Novavax ancestral or BA.1 spike booster vaccines against SARS-CoV-2 BA.5 infection in nonhuman primates
Authors: Nanda Kishore Routhu, Samuel David Stampfer, Lilin Lai, Akil Akhtar, Xin Tong, Dansu Yuan, Taras M. Chicz, Ryan P. McNamara, Kishor Jakkala, Meredith E. Davis-Gardner, E. Lovisa St Pierre, Brandon Smith, Kristyn Moore Green, Nadia Golden, Breanna Picou, Sherrie M. Jean, Jennifer Wood, Joyce Cohen, Ian N. Moore, Nita Patel, Mimi Guebre-Xabier, Gale Smith, Greg Glenn, Pamela A. Kozlowski, Galit Alter, Rafi Ahmed, Mehul S. Suthar, Rama Rao Amara
Journal: Science Immunology (2023)

Omicron SARS-CoV-2 variants escape vaccine-induced neutralizing antibodies and cause nearly all current COVID-19 cases. Here, we compared the efficacy of three booster vaccines against Omicron BA.5 challenge in rhesus macaques: mRNA-1273, the Novavax ancestral spike protein vaccine (NVX-CoV2373), or Omicron BA.1 spike protein version (NVX-CoV2515). All three booster vaccines induced a strong BA.1 cross-reactive binding antibody and changed immunoglobulin G (Ig) dominance from IgG1 to IgG4 in the serum. All three booster vaccines also induced strong and comparable neutralizing antibody responses against multiple variants of concern, including BA.5 and BQ.1.1, along with long-lived plasma cells in the bone marrow. The ratio of BA.1 to WA-1 spike-specific antibody-secreting cells in the blood was higher in NVX-CoV2515 animals compared with NVX-CoV2373 animals, suggesting a better recall of BA.1-specific memory B cells by the BA.1 spike-specific vaccine compared with the ancestral spike-specific vaccine. Further, all three booster vaccines induced low levels of spike-specific CD4 but not CD8 T cell responses in the blood. After challenge with SARS-CoV-2 BA.5 variant, all three vaccines showed strong protection in the lungs and controlled virus replication in the nasopharynx. In addition, both Novavax vaccines blunted viral replication in nasopharynx at day 2. The protection against SARS-CoV-2 BA.5 infection in the upper respiratory airways correlated with binding, neutralizing, and ADNP activities of the serum antibody. These data have important implications for COVID-19 vaccine development, because vaccines that lower nasopharyngeal virus may help to reduce transmission.
Prostate organoids: emerging experimental tools for translational research
Authors: Michael Beshiri, Supreet Agarwal, Juan Juan Yin, Kathleen Kelly
Journal: Journal of Clinical Investigation (2023)

Organoid technology has provided new translational research opportunities in oncology, in part by enabling the development of patient-representative living biobanks. Prostate cancer research historically has been constrained to a small number of in vitro models, limiting the ability to translate experimental conclusions for contemporary, heterogeneous patient populations. The facility of organoid culture methods to maintain luminal prostate epithelia, the common lineage of prostate cancers, has greatly expanded the phenotypic and genotypic diversity of available tractable models, including luminal stem/progenitor cells and progressive patient-derived cancers. Biobanks of patient prostate cancer organoids enable increased accuracy in predicting therapeutic efficacy and informative clinical trial designs. Here, we discuss how prostate organoid technology is currently being used, the promising areas of future therapeutic applications, and the current obstacles to be overcome.
The Economic Burden of Racial, Ethnic, and Educational Health Inequities in the US
Authors: Thomas A. LaVeist, Eliseo J. Pérez-Stable, Patrick Richard, Andrew Anderson, Lydia A. Isaac, Riley Santiago, Celine Okoh, Nancy Breen, Tilda Farhat, Assen Assenov, Darrell J. Gaskin
Journal: JAMA (2023)

Health inequities exist for racial and ethnic minorities and persons with lower educational attainment due to differential exposure to economic, social, structural, and environmental health risks and limited access to health care.To estimate the economic burden of health inequities for racial and ethnic minority populations (American Indian and Alaska Native, Asian, Black, Latino, and Native Hawaiian and Other Pacific Islander) and adults 25 years and older with less than a 4-year college degree in the US. Outcomes include the sum of excess medical care expenditures, lost labor market productivity, and the value of excess premature death (younger than 78 years) by race and ethnicity and the highest level of educational attainment compared with health equity goals.Analysis of 2016-2019 data from the Medical Expenditure Panel Survey (MEPS) and state-level Behavioral Risk Factor Surveillance System (BRFSS) and 2016-2018 mortality data from the National Vital Statistics System and 2018 IPUMS American Community Survey. There were 87 855 survey respondents to MEPS, 1 792 023 survey respondents to the BRFSS, and 8 416 203 death records from the National Vital Statistics System.In 2018, the estimated economic burden of racial and ethnic health inequities was $421 billion (using MEPS) or $451 billion (using BRFSS data) and the estimated burden of education-related health inequities was $940 billion (using MEPS) or $978 billion (using BRFSS). Most of the economic burden was attributable to the poor health of the Black population; however, the burden attributable to American Indian or Alaska Native and Native Hawaiian or Other Pacific Islander populations was disproportionately greater than their share of the population. Most of the education-related economic burden was incurred by adults with a high school diploma or General Educational Development equivalency credential. However, adults with less than a high school diploma accounted for a disproportionate share of the burden. Although they make up only 9% of the population, they bore 26% of the costs.The economic burden of racial and ethnic and educational health inequities is unacceptably high. Federal, state, and local policy makers should continue to invest resources to develop research, policies, and practices to eliminate health inequities in the US.
Patterns of Manufacturer Coupon Use for Prescription Drugs in the US, 2017-2019
Authors: So-Yeon Kang, Angela Liu, Gerard Anderson, G. Caleb Alexander
Journal: JAMA Network Open (2023)

Although manufacturer-sponsored coupons are commonly used, little is known about how patients use them within a treatment episode.To examine when and how frequently patients use manufacturer coupons during a treatment episode for a chronic condition, and to characterize factors associated with more frequent use.This is a retrospective cohort study of a 5% nationally representative sample of anonymized longitudinal retail pharmacy claims data from October 1, 2017, to September 30, 2019, obtained from IQVIA's Formulary Impact Analyzer. The data were analyzed from September to December 2022. Patients with new treatment episodes using at least 1 manufacturer coupon over a 12-month period were identified. This study focused on patients with 3 or more fills for a given drug and characterized the association of the outcomes of interest with patient, drug, and drug class characteristics.The primary outcomes were (1) the frequency of coupon use, measured as the proportion of prescription fills accompanied by manufacturer coupon within the treatment episode, and (2) the timing of first coupon use relative to the first prescription fill within the treatment episode.A total of 36 951 treatment episodes accounted for 238 474 drug claims and 35 352 unique patients (mean [SD] age, 48.1 [18.2] years; 17 676 women [50.0%]). Among these episodes, nearly all instances (35 103 episodes [95.0%]) of first coupon use occurred within the first 4 prescription fills. Approximately two-thirds of treatment episodes (24 351 episodes [65.9%]) used a coupon for the incident fill. Coupons were used for a median (IQR) of 3 (2-6) fills. The median (IQR) proportion of fills with a coupon was 70.0% (33.3%-100.0%), and many patients discontinued the drug after the last coupon. After adjustment for covariates, there was no significant association between an individual's out-of-pocket costs or neighborhood-level income and the frequency of coupon use. The estimated proportion of fills with a coupon was greater for products in competitive (19.5% increase; 95% CI, 2.1%-36.9%) or oligopolistic (14.5% increase; 95% CI, 3.5%-25.6%) markets than monopoly markets when there is only 1 drug in the therapeutic class.In this retrospective cohort analysis of individuals receiving pharmaceutical treatment for chronic diseases, the frequency of manufacturer-sponsored drug coupon use was associated with the degree of market competition, rather than patients' out-of-pocket costs.
Epigenetic reprogramming of Runx3 reinforces CD8 + T-cell function and improves the clinical response to immunotherapy
Authors: Zongzhi Liu, Xiang Li, Yibo Gao, Jiejie Liu, Yating Feng, Yang Liu, Junyun Wang, Chunmeng Wang, Dongrui Wang, Jie He, Weidong Han, Qian Mei, Yingli Sun
Journal: Molecular Cancer (2023)

Abstract Background Checkpoint blockade immunotherapy, represented by PD-1 or PD-L1 antibody treatment, has been of tremendous success in clinical practice. However, the low clinical response rate and lack of biomarkers for prediction of the immune response limit the clinical application of anti-PD-1 immunotherapy. Our recent work showed that a combination of low-dose decitabine and PD-1-ab significantly improved the complete response (CR) rate of cHL patients from 32 to 71%, which indicates that there is a significant correlation between epigenetic regulation and the clinical response to immunotherapy. Methods We recruited two groups of Hodgkin lymphoma patients who were treated with anti-PD-1 and DAC+anti-PD-1. CD8+ T cells were isolated from the patients' peripheral blood, DNA methylation was analyzed by EPIC, the expression profile was analyzed by RNA-seq, and multigroup analysis was performed with IPA and GSEA functional annotations. We explored the effect of DAC on the function of CD8+ T cells in the blood, spleen, tumor and lymph nodes using a mouse model. Furthermore, we explored the function of Tils in the tumor microenvironment. Then, we constructed Runx3-knockout mice to confirm the T-cell-specific function of Runx3 in CD8+ T cells and analyzed various subtypes of T cells and cytokines using mass cytometry (CyTOF). Results Multiomics analysis identified that DNA methylation reprogramming of Runx3 was a crucial mediator of CD8+ T-cell function. Multiomics data showed that reversal of methylation of the Runx3 promoter promoted the infiltration of CD8+ TILs and mitigated the exhaustion of CD8+ T cells. Furthermore, experiments on tissue-specific Runx3-knockout mice showed that Runx3 deficiency reduced CD8+ T infiltration and the differentiation of effector T and memory T cells. Furthermore, Runx3 deficiency significantly decreased CCR3 and CCR5 levels. Immunotherapy experiments in Runx3 conditional knockout mice showed that DAC could not reverse the resistance of anti-PD-1 in the absence of Runx3. Moreover, both our clinical data and data from TISIDB showed that Runx3 could be a potential biomarker for immunotherapy to predict the clinical response rate. Conclusion We demonstrate that the DNA methylation of Runx3 plays a critical role in CD8+ T-cell infiltration and differentiation during decitabine-primed PD-1-ab immunotherapy, which provides a supporting mechanism for the essential role of epiregulation in immunotherapy.
Viral vector–mediated expression of NaV1.1, after seizure onset, reduces epilepsy in mice with Dravet syndrome
Authors: Saja Fadila, Bertrand Beucher, Iria González Dopeso-Reyes, Anat Mavashov, Marina Brusel, Karen Anderson, Caroline Ismeurt, Ethan M. Goldberg, Ana Ricobaraza, Ruben Hernandez-Alcoceba, Eric J. Kremer, Moran Rubinstein
Journal: Journal of Clinical Investigation (2023)

Dravet syndrome (DS), an intractable childhood epileptic encephalopathy with a high fatality rate, is typically caused by loss-of-function mutations in one allele of SCN1A, which encodes NaV1.1, a 250-kDa voltage-gated sodium channel. In contrast to other epilepsies, pharmaceutical treatment for DS is limited. Here, we demonstrate that viral vector-mediated delivery of a codon-modified SCN1A open reading frame into the brain improves DS comorbidities in juvenile and adolescent DS mice (Scn1aA1783V/WT). Notably, bilateral vector injections into the hippocampus and/or the thalamus of DS mice increased survival, reduced the occurrence of epileptic spikes, provided protection from thermally induced seizures, corrected background electrocorticographic activity and behavioral deficits, and restored hippocampal inhibition. Together, our results provide a proof of concept for the potential of SCN1A delivery as a therapeutic approach for infants and adolescents with DS-associated comorbidities.
Maternal microbe-specific modulation of the offspring microbiome and development during pregnancy and lactation
Authors: Min Tian, Qihui Li, Tenghui Zheng, Siwang Yang, Fang Chen, Wutai Guan, Shihai Zhang
Journal: Gut Microbes (2023)

The maternal microbiome is essential for the healthy growth and development of offspring and has long-term effects later in life. Recent advances indicate that the maternal microbiome begins to regulate fetal health and development during pregnancy. Furthermore, the maternal microbiome continues to affect early microbial colonization via birth and breastfeeding. Compelling evidence indicates that the maternal microbiome is involved in the regulation of immune and brain development and affects the risk of related diseases. Modulating offspring development by maternal diet and probiotic intervention during pregnancy and breastfeeding could be a promising therapy in the future. In this review, we summarize and discuss the current understanding of maternal microbiota development, perinatal microbial metabolite transfer, mother-to-infant microbial transmission during/after birth and its association with immune and brain development as well as corresponding diseases.
Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
Authors: Winnie L. Kan, Urmi Dhagat, Kerstin B. Kaufmann, Timothy R. Hercus, Tracy L. Nero, Andy G.X. Zeng, John Toubia, Emma F. Barry, Sophie E. Broughton, Guillermo A. Gomez, Brooks A. Benard, Mara Dottore, Karen S. Cheung Tung Shing, Héléna Boutzen, Saumya E. Samaraweera, Kaylene J. Simpson, Liqing Jin, Gregory J. Goodall, C. Glenn Begley, Daniel Thomas, Paul G. Ekert, Denis Tvorogov, Richard J. D'Andrea, John E. Dick, Michael W. Parker, Angel F. Lopez
Journal: Cancer Discovery (2023)

Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the individual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. This article is highlighted in the In This Issue feature, p. 1749.
Far upstream element‐binding protein 1 confers lobaplatin resistance by transcriptionally activating PTGES and facilitating the arachidonic acid metabolic pathway in osteosarcoma
Authors: Qiong Ma, Jin Sun, Huan Wang, Chengpei Zhou, Chenyu Li, Yonghong Wu, Yanhua Wen, Xiaoyu Zhang, Xingguang Ren, Zheng Guo, Li Gong, Wei Zhang
Journal: MedComm (2023)

Drug resistance is a major obstacle in cancer treatment and recurrence prevention and leads to poor outcomes in patients suffering from osteosarcoma. Clarification of the mechanism of drug resistance and exploration of effective strategies to overcome this obstacle could lead to clinical benefits for these patients. The expression of far upstream element-binding protein 1 (FUBP1) was found to be markedly elevated in osteosarcoma cell lines and clinical specimens compared with osteoblast cells and normal bone specimens. High expression of FUBP1 was correlated with a more aggressive phenotype and a poor prognosis in osteosarcoma patients. We found that overexpression of FUBP1 confers lobaplatin resistance, whereas the inhibition of FUBP1 sensitizes osteosarcoma cells to lobaplatin-induced cytotoxicity both in vivo and in vitro. Chromatin immunoprecipitation-seq and RNA-seq were performed to explore the potential mechanism. It was revealed that FUBP1 could regulate the transcription of prostaglandin E synthase (PTGES) and subsequently activate the arachidonic acid (AA) metabolic pathway, which leads to resistance to lobaplatin. Our investigation provides evidence that FUBP1 is a potential therapeutic target for osteosarcoma patients. Targeting FUBP1, its downstream target PTGES and the AA metabolic pathway may be promising strategies for sensitizing chemoresistant osteosarcoma cells to lobaplatin.
Histone deacetylase‐based dual targeted inhibition in multiple myeloma
Authors: Angelica Ferro, Evangelia Pantazaka, Constantinos M. Athanassopoulos, Muriel Cuendet
Journal: Medicinal Research Reviews (2023)

Despite enormous advances in terms of therapeutic strategies, multiple myeloma (MM) still remains an incurable disease with MM patients often becoming resistant to standard treatments. To date, multiple combined and targeted therapies have proven to be more beneficial compared to monotherapy approaches, leading to a decrease in drug resistance and an improvement in median overall survival in patients. Moreover, recent breakthroughs highlighted the relevant role of histone deacetylases (HDACs) in cancer treatment, including MM. Thus, the simultaneous use of HDAC inhibitors with other conventional regimens, such as proteasome inhibitors, is of interest in the field. In this review, we provide a general overview of HDAC-based combination treatments in MM, through a critical presentation of publications from the past few decades related to in vitro and in vivo studies, as well as clinical trials. Furthermore, we discuss the recent introduction of dual-inhibitor entities that could have the same beneficial effects as drug combinations with the advantage of having two or more pharmacophores in one molecular structure. These findings could represent a starting-point for both reducing therapeutic doses and lowering the risk of developing drug resistance.
Ferroptosis: the vulnerability within a cancer monster
Authors: Wanqing Xie, Shivani Agarwal, Jindan Yu
Journal: Journal of Clinical Investigation (2023)

Treatment-resistant cancer, such as neuroendocrine prostate cancer (NEPC), is a lethal disease with limited therapeutic options. RB1 is a tumor suppressor gene that is lost in a majority of NEPC tumors. In this issue of the JCI, Wang and colleagues examined how RB1 loss may sensitize cancer cells to ferroptosis inducers through elevation of ACSL4, a key enzyme that promotes lipid peroxidation and triggers ferroptosis. We discuss a high potential of RB1-deficient cells to undergo ferroptosis due to the elevation of ACSL4. This is normally kept in check by abundant expression of GPX4, an antioxidant enzyme, in cancer cells. This balance, however, is tilted by GPX4 inhibitors, leading to massive ferroptosis. We highlight possible therapeutic strategies that exploit this inherent vulnerability for targeting RB1-deficient, treatment-resistant cancer.